Pyrimidine derivatives for the treatment of abnormal cell growth

Abstract

The present invention relates to a compound of the formula 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula and R 1 , R 2 , R 13 , A, K, M, L 1 , L 2 , X, Y 1 , Y 2 , Q, salt thereof, wherein R 1 , R 2 , R 13 , A, K, L 1 , L 2 , W, X, Z 1 , Z 2 , Y 1 , Y 2 , Z 1 , Z 2 , M, Q, W, X, m, p and q are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. The invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

1. A compound selected from the group consisting of:
 1-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-hydroxy-ethanone, 
 2-Amino-1-[6-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide, 
 6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,2R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid ethyl-amide, 
 1-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-methoxy-ethanone, 
 [6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-cyclopropyl-methanone, 
 1-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 N4-Cyclobutyl-N2-[(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 
 (+/−)-1-[6-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclopropylamino-5-methyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclopropylamino-5-fluoro-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Ethylamino-5-methyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Ethylamino-5-fluoro-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-ethylamino-5-chloro-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-{6-[5-Fluoro-4-((S)-2-methoxymethyl-pyrrolidin-1-yl)-pyrimidin-2-ylamino]-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl}-ethanone, 
 N4-Cyclobutyl-N2-[(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 
 1-[6-(4-Cyclobutylamino-5-methyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide, 
 [6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-acetic acid methyl ester, 
 [6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-(R)-pyrrolidin-2-yl-methanone, 
 [6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-cyclopropyl-methanone, 
 1-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-methoxy-ethanone, 
 6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalene-9-carboxylic acid isopropyl-amide, 
 1-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-methylamino-ethanone, 
 1-[6-(5-Chloro-4-cyclobutylamino-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclobutylamino-5-fluoro-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclobutylamino-5-ethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 1-[6-(4-Cyclobutylamino-5-methyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-ethanone, 
 N4-Cyclopropyl-N2-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl-5-trifluoromethyl-pyrimidine-2,4-diamine, 
 N4-Cyclopropyl-N2-[(1R,4S)-9-methanesulfonyl-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-6-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine, 
 1-[6-(4-Cyclopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1R,4S)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-methoxy-ethanone, 
 (+/−)-1-{6-[4-(2-Methoxy-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl}-ethanone, 
 (+/−)-2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-N,N-dimethyl-acetamide, 
 (+/−)-N-{2-[6-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide, 
 
       and pharmaceutically acceptable salts thereof of each of the foregoing compounds. 
     
     
       2. A compound of the following formula 
       
         
           
           
               
               
           
         
         which is N-{2-[6-(4-cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-(1S,4R)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl]-2-oxo-ethyl}-acetamide or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. A pharmaceutical composition comprising a compound or salt according to  claim 2 , and a pharmaceutically acceptable carrier.